We, herein, report two cases of EDS type VIA with neonatal hypotonia, and prenatal brain stroke.

Two siblings born to third degree consanguineous parents are reported. When Case 1 was 4½ years old, her sister (Case 2) was born. Table I reports the description of the two cases. An EDS diagnosis was suspected when Case 1 was two years old. The diagnosis was based on joint hypermobility; delayed motor development (walking at 24 months, level 2 on Bimanual Fine Function; and on Gross Motor Function Classification System scales at 24 months). Suggestive facial dysmorphology, such as blepharochalasis, drooping cheeks, bluish sclera, tallness with a Marfanoid habitus, and arachnodactyly also contributed to this diagnosis. Her skin was hyperelastic with multiple bruises and a lassis venular. Furthermore she had a ligament laxity at 8/9.

TABLE I  Description of Two Cases  of Kyphoscolitic Ehlers-Danlos Syndrome  

After the second child’s birth, our work-up used DNA blood sampling as well as a skin biopsy taken from the Case 1 to investigate classic (II) and vascular (IV) types of EDS. The COL3A1, TGFBR1, and TGBR2 genes exhibited no sequence abnormality. By using DNA blood samples from sisters, all coding exons and the neighboring intronic regions of the PLOD1 gene were amplified from the DNA by PCR (polymerase chain reaction). These were then sequenced directly with flanking primers and PLOD1 gene dosage analysis was performed by quantitative Real Time PCR including 19 amplicons in exon 1-19. We then took a blood sample from the parents. By qPCR a duplication of exons　10 and 16 was detected in the PLOD1 gene, confirming the diagnosis of EDS type VIA in both sisters. This duplication was found present on both alleles.

(a)                                                             (b) Fig. 1 Brain MRI of cases: (a) patient 1. Axial T2 sequence showing an cerebral intraventricular hemorrhage (arrow head) in T2 hypointensity, a subependymal hemorrhage (white arrow) and hemorrhagic infarction of the right centrum semiovale with diffusion restriction on axial DWI MRI images. (b) patient 2. Axial T2 sequences showing ischemic lesions of the anterior limb of the left internal capsule and right caudate nucleus, hypoT2 linear images may result of the periventricular and lenticulostriate vessels hemorraghic infarction (thin black arrow).

Discussion

Our report illustrates a rare phenotype of EDS type VIA with a prenatal brain stroke. When a combination of prenatal brain stroke and neonatal hypotonia is noted, the possibility of EDS should always be contemplated. Finding the cause of this hypotonia requires a rigorous diagnostic approach using the Dubowitz algorithm [3]. Neonatal hypotonia consistently appeared as a clinical symptom in a review of 12 cases with variations of kyphoscoliotic EDS phenotype [1].

The presence of prenatal brain stroke and the absence of kyphoscoliosis noted in the neonatal period evoke an EDS type IV. This disease, often found in young adults, is linked to mutations in COL3A1 gene and has a different phenotype [4]. An autosomal recessive mode of inheritance is most probable, especially with consanguineous parents, and we carried out COL3A1 genetic screening by molecular analysis of skin biopsies. These proved to be negative, and we therefore discarded a diagnosis of EDS type IV [5].

The key diagnostic criteria were severe hypotonia, tendon laxity, scoliosis and scleral fragility. Assaying the enzymatic activity of PLOD from a skin biopsy showed 10-16 exon gene duplication. Neither strokes nor hip dislocation are typical of this syndrome with hip dislocation being found in only 25% of EDS type VI cases [1]. Similarly, in EDS type VI there is a possibility of vascular rupture. A prenatal case is described in a recent review of 15 patients and in an index case reported by Yis, et al. [6]. Tosun, et al. [2] suggest that although one of their patient’s subdural and intraparenchymal hemorrhage could be attributed to a breech delivery or difficult birth, the patient’s abnormal collagen structure may be a facilitating factor. Finally vascular ruptures are probably underestimated in this syndrome. In particular, 15% of mutant mouse PLOD -/- die of aortic dissections due to smooth muscle and collagen degeneration in the vessel wall [7]. Thus, a prenatal vascular event without any etiology with hypotonia and kyphosis ought to prompt a search for EDS type VI besides, COL4A1/A2 mutations without EDS were already evaluated in the etiology of intraventricular hemorrhage detected in utero [4].

Contributors: MZC: participated in the interpretation and writing of the manuscript; BT, CG, SC: participated in the patient management, and interpretation and writing of the manuscript. All the authors approved the final manuscript.

1. Rohrbach M, Vandersteen A, Yiº U, Serdaroglu G, Ataman E, Chopra M, et al. Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation. Orphanet J Rare Dis. 2011;23;6-46.

2. Tosun A, Kurtgoz S, Dursun S, Bozkurt G. A case of Ehlers-Danlos Syndrome Type VIA with a novel PLOD1 gene mutation. Pediat Neurol. 2014;51:566-9.

3. Dubowitz L, Ricciw D, Mercuri E. The Dubowitz neurological examination of the full-term newborn. Ment Retard Dev Disabil Res Rev. 2005;11:52-60.

4. Parapia LA, Jackson C. Ehlers-Danlos syndrome　: A historical review. Br J Haematol. 2008;141:32-5.

5. Kutuk MS, Balta B, Kodera H, Matsumoto N, Saitsu H, Doganay S, et al. Is there relation between COL4A1/A2 mutations and antenatally detected fetal intraventricular hemorrhage? Childs Nerv Syst. 2014;30:419-24.

6. Yiº U, Dirik E, Chambaz C, Steinmann B, Giunta C. Differential diagnosis of muscular hypotonia in infants: The kyphoscoliotic type of Ehlers–Danlos syndrome (EDS VI). Neuromus Disord. 2008;18:210-4.